Central Neurocytoma

Key Points at a Glance

Key Points of This Disease

• Central neurocytoma (CN) is a rare benign brain tumor (WHO grade II) that primarily arises in the lateral ventricles, accounting for 0.1–0.5% of all brain tumors.
• It occurs predominantly in young adults aged 20–40 years, with no sex predilection.
• The main pathology is increased intracranial pressure due to obstructive hydrocephalus, with headache, nausea, and papilledema being typical symptoms.
• Visual symptoms (blurred vision, decreased visual acuity, diplopia) are present in 37% of patients, and up to 43% have papilledema.
• Immunohistochemical testing, particularly positivity for synaptophysin, is essential for definitive diagnosis.
• Gross total resection (GTR) is the standard treatment, and the 5-year survival rate after GTR exceeds 90%, indicating a favorable prognosis.
• Molecular biological techniques (DNA methylation profiling) are increasingly revealing cases where conventional pathological diagnoses are revised.

1. What is Central Neurocytoma?

Central neurocytoma (CN) is a benign neuronal tumor of the central nervous system (CNS), corresponding to WHO grade II. It was first described by Hassoun et al. in 1982, making it a relatively new disease entity. In the 2021 WHO 5th edition classification, it is categorized under neuronal and mixed neuronal–glial tumors. ³⁾

CN is a rare tumor, accounting for 0.1–0.5% of all brain tumors and less than 1% of all intracranial tumors. ^{2, 3, 4)} The site of origin is the lateral ventricle in 50% of cases, lateral ventricle plus third ventricle in 13%, third ventricle alone in 3%, and rarely the fourth ventricle or extraventricular sites. ³⁾ The median tumor diameter is 4.2 cm. ³⁾

The peak age of onset is young adults aged 20–40 years (3rd–4th decades), with no sex difference. ^{2, 3)} Reports are more common in Asian populations (e.g., Korea, India, Japan) than in Caucasian populations. Reports from Africa are extremely rare, with only two cases in the literature. ³⁾

Regarding the cell of origin, hypotheses suggest derivation from neuronal cells of the septum pellucidum or subependymal cells of the lateral ventricle, but no definitive conclusion has been established. ^{1, 3)}

Q How rare is central neurocytoma?

A

It is a rare tumor accounting for 0.1–0.5% of all brain tumors. It occurs predominantly in young adults aged 20–40 years, with no sex difference. Reports are relatively more common in Asian populations. ³⁾

2. Main Symptoms and Clinical Findings

Subjective Symptoms

The most common symptom is headache, caused by tumor-induced obstruction of the foramen of Monro leading to obstructive hydrocephalus and increased intracranial pressure. Multiple case reports document progressive headache over weeks to months as the initial symptom. ^{1, 2, 4, 5)}

• Headache: Due to obstructive hydrocephalus. Often a dull frontal headache that worsens with movement or changes in position. ⁴⁾
• Nausea and vomiting: Frequently associated with increased intracranial pressure. ^{2, 4)}
• Visual disturbances: 37% of CN patients report visual complaints (in a series of 32 cases), including blurred vision, decreased visual acuity, and diplopia. ²⁾
• Cognitive and behavioral changes: Decreased concentration and forgetfulness have been reported. ⁴⁾
• Ataxia: May occur when the tumor is large. ²⁾
• Seizures: Rarely, they may be the initial symptom. ³⁾
• Hemiparesis: Can occur due to midline shift and compression of brain parenchyma from a large mass, but this is an atypical presentation. ³⁾

Specialist Supplement

When a tumor arises in the lateral ventricle, it may cause olfactory and gustatory abnormalities, homonymous hemianopia, and homonymous quadrantanopia. The diversity of symptoms can delay diagnosis.

Clinical Findings

Papilledema (optic disc swelling) is the most important ophthalmologic finding, observed in up to 43% of cases. ²⁾ It results from increased intracranial pressure leading to elevated pressure in the subarachnoid space around the optic nerve, constriction of the nerve, and stagnation of axoplasmic flow.

Fundus examination reveals the following findings:

• Redness and swelling of the optic disc: Seen bilaterally. The margins become indistinct.
• Hemorrhage and exudates on and around the optic disc: Changes due to inflammatory spread.
• Dilation of retinal veins: Reflects venous stasis.

In the early stage, patients often complain only of transient visual obscuration lasting a few seconds. If papilledema persists for several months, hemorrhages and exudates are absorbed, and inferonasal or concentric visual field constriction occurs. Subsequently, visual acuity decline becomes apparent. Regular monitoring of fundus findings is important.

There is also a risk of prolonged papilledema → increased intraocular pressure → transient optic nerve ischemia → sudden vision loss. Visual field defects due to the mass effect of the tumor have also been reported. ²⁾

Abducens nerve palsy (false localizing sign) can occur as a non-localizing neurological symptom associated with generalized increased intracranial pressure.

Q Why do visual symptoms occur in central neurocytoma?

A

The tumor obstructs the foramen of Monro, causing obstructive hydrocephalus and increased intracranial pressure. This raises pressure in the subarachnoid space around the optic nerve, leading to stagnation of axoplasmic flow and formation of papilledema. Visual symptoms (blurred vision, decreased visual acuity) are observed in 37% of patients, and up to 43% have papilledema. ²⁾

3. Causes and Risk Factors

No established risk factors for CN have been reported to date. Because it is a rare tumor, epidemiological studies are limited, and associations with genetic or environmental factors remain unclear.

Regarding the cell of origin, the prevailing hypothesis is that CN arises from bipotential progenitor cells embedded in the periventricular matrix. ¹⁾ At a small stage, the tumor attaches to the lateral ventricular wall with a broad base, with only mild attachment to the septum pellucidum. As the tumor grows, it extends toward the septum pellucidum and may reach the contralateral lateral ventricle. ¹⁾

Recent knowledge has accumulated on molecular biological features, revealing that CN and EVN (extraventricular neurocytoma) have distinct DNA methylation profiles and copy number profiles. ¹⁾ EWSR1-ATF1 fusion gene and MUTYH mutations have been reported in some CN cases, but no definitive driver mutation has been identified.

Prevention and Daily Care

There is no established prevention method. If symptoms such as headache, nausea, or decreased vision persist in young adults, please consult a neurologist or neurosurgeon early.

4. Diagnosis and Examination Methods

Imaging Diagnosis

On CT, it appears as an isodense to hyperdense mass with homogeneous contrast enhancement. Calcification is seen in about 50% of cases. When the tumor is large, cystic areas may be present. ^{3, 4)}

MRI is the most important imaging study.

• T1-weighted imaging: Iso- to hypointense. ^{2, 4)}
• T2-weighted imaging: Hyperintense, heterogeneous. ²⁾
• Contrast enhancement: Moderate to strong enhancement. ^{1, 4)}
• Flow voids: Reflect the rich vascularity of the tumor. ²⁾
• DWI: Often shows no restricted diffusion. ⁴⁾
• Perfusion imaging: Shows moderate vascularity. ⁴⁾
• Typical morphology: A well-defined solid-cystic mass attached to the septum pellucidum and occupying the lateral ventricle. ^{2, 4)}

Main differential diagnoses on imaging include subependymoma, ependymoma, intraventricular meningioma, choroid plexus papilloma, glioma, malignant teratoma, and astrocytoma. ^{2, 4)}

Histopathological Diagnosis

Definitive diagnosis is based on histological examination of stereotactic biopsy or surgical specimens.

Light microscopic findings are as follows:

• Uniform small round cells: Arranged at moderate density, giving a monotonous appearance. ³⁾
• Honeycomb pattern: Scant cytoplasm and punctate chromatin give an appearance similar to oligodendroglioma. ^{1, 2, 3)}
• Perinuclear clearing: So-called “fried egg” appearance. ³⁾
• Fibrillary (neuropil-like) matrix: Characteristic fibrillary background between tumor cells. ^{1, 2, 3)}
• Thin branching capillaries (chicken wire pattern): Forming a rich vascular network. ^{2, 3)}
• Perivascular pseudorosettes: Also called pineocytomatous rosettes. ^{1, 2, 3)}
• Calcification: May include psammomatous calcification. ^{1, 2, 3)}
• No atypia, mitosis, or necrosis: Defining features of typical non-atypical CN.

Intraoperative rapid diagnosis considerations

CN can closely resemble oligodendroglioma or clear cell ependymoma in cell morphology, making differentiation difficult on intraoperative crush smears or frozen sections. ²⁾ Since the result of intraoperative rapid diagnosis directly affects the extent of resection, careful judgment is required. Immunohistochemical examination is essential for final diagnosis.

Immunohistochemistry

Useful immunostaining markers for differentiation are shown below.

Marker	CN	Oligodendroglioma	Ependymoma
Synaptophysin	Diffuse positive	Negative to weak positive	Negative to weak positive
NeuN	Positive	Negative	Negative
GFAP	Tumor cells negative	Negative to weakly positive	Positive
EMA	Negative	Negative	Positive (dot-like)
OLIG2	Negative	Positive	Negative to weakly positive

Diffuse positivity for synaptophysin is the most reliable diagnostic marker. ^{1, 2, 3, 4)} Positivity for NeuN and NSE also supports neuronal differentiation. ^{2, 3, 4)} GFAP is negative in the tumor cells themselves, but reactive astrocytes mixed in show positivity. ^{1, 2, 3)}

The Ki-67/MIB-1 proliferation index is important for prognosis assessment. In typical non-atypical CN, it is often less than 2–3%. ^{2, 3, 4)} Cases with MIB-1 LI <2% have a 22% recurrence rate, whereas those with MIB-1 LI >2% have a 63% recurrence rate. ³⁾ If it exceeds 5%, the possibility of atypical CN should be considered.

Molecular Diagnosis

In recent years, DNA methylation profiling has emerged as a powerful tool for distinguishing CN from EVN (extraventricular neurocytoma) and for definitive diagnosis. ¹⁾ Even when histological findings are typical, cases have been reported that are reclassified as tumors of a different methylation class. The FGFR1-TACC1 fusion gene is a characteristic marker of EVN and may also be detected in rare tumors that appear to be CN. ¹⁾

Q What is the most important test for definitive diagnosis of central neurocytoma?

A

Immunohistochemical examination using stereotactic biopsy or surgical specimens is key to definitive diagnosis. Diffuse positivity for synaptophysin is the most reliable marker, and the pattern of NeuN positivity, GFAP negativity (in tumor cells), and OLIG2 negativity supports differentiation from oligodendroglioma and ependymoma. ^{1, 2)}

5. Standard Treatment

Surgical Treatment

Gross total resection (GTR) is the standard treatment. ^{1, 2, 3, 4, 5)} If GTR is achieved, observation without adjuvant therapy is often possible.

GTR is achievable in 30–50% of cases. The most common surgical approach is the anterior interhemispheric transcallosal approach, and support from a neuronavigation system is useful. ^{3, 4, 5)} In recent years, neuroendoscopic resection has also been reported. ⁵⁾

Major treatment outcomes by treatment modality are shown below.

Treatment	5-Year Survival Rate	5-Year Local Control Rate
GTR alone	>90% to 99%1, 4)	100% (Schild 1997, 32 cases)3)
STR alone	86%2)	Low (adjuvant therapy required)
STR + adjuvant radiotherapy	90% (median follow-up 56 months)3)	—

Subtotal resection (STR) carries a high risk of recurrence and requires postoperative adjuvant therapy.²⁾

Radiotherapy

After STR or for residual tumor, postoperative adjuvant radiotherapy is administered to prevent tumor progression and recurrence.^{1, 2)} The median dose is 54 Gy (range 50–60 Gy).³⁾ Both fractionated radiotherapy and stereotactic radiosurgery (SRS) have been reported to be effective, but the superiority of one over the other has not been established.²⁾

Specialist supplement

For CN with low Ki-67 (typically <2–3%) after GTR, radiotherapy may be omitted and observation chosen.⁴⁾ The indication for adjuvant radiotherapy is determined by considering the extent of resection, proliferation index, age, and patient preference.

Chemotherapy

Chemotherapy is limited to inoperable cases resistant to surgery and radiotherapy, and is not widely used or studied.²⁾ The main regimens used are as follows:

• PCV therapy: procarbazine + lomustine + vincristine.²⁾
• Topotecan, carboplatin, ifosfamide combination.²⁾
• Carmustine, prednisone, vincristine, cisplatin. ³⁾

The response to chemotherapy is not well characterized, and its efficacy is unclear. ³⁾

Postoperative complications

A rare but notable complication after the transcallosal approach is corpus callosum swelling. ⁵⁾ The main cause is interstitial edema, which often resolves spontaneously without intervention, and long-term cognitive decline is usually not observed (confirmed by 2-year follow-up with WAIS-III). ⁵⁾ Other reported complications include acute hydrocephalus, tension pneumocephalus, and postoperative status epilepticus. ⁵⁾

Q What is the treatment if total resection is not possible?

A

After subtotal resection (STR), the risk of recurrence is high, so postoperative adjuvant radiotherapy is routinely added. The median dose is 54 Gy (range 50–60 Gy), with reported 5-year overall survival of 90% and 5-year progression-free survival of 76% (median follow-up 56 months). ³⁾ Chemotherapy is reserved for cases resistant to surgery and radiotherapy.

6. Pathophysiology and detailed pathogenesis

CN is presumed to originate from bipolar progenitor cells embedded in the periventricular matrix. ¹⁾ Positivity for synaptophysin and NeuN demonstrates neuronal differentiation, but the exact histogenesis of the tumor remains incompletely understood.

Pathophysiology of increased intracranial pressure is as follows:

• Primary mechanism: Compression of brain parenchyma due to the mass effect of the tumor itself.
• Secondary mechanism: Obstruction of the foramen of Monro by the tumor → obstructive hydrocephalus → ventricular dilation.
• Tertiary mechanism: Increased intracranial pressure due to peritumoral brain edema.

These three factors interact to cause symptoms of increased intracranial pressure such as headache, nausea, and papilledema.

Mechanism of papilledema formation involves the following steps: increased intracranial pressure → elevated pressure in the optic nerve subarachnoid space → constriction of the optic nerve sheath → stagnation of axoplasmic flow → vascular compression in the prelaminar region → papilledema formation. If papilledema persists, axonal degeneration and vascular damage progress, leading to irreversible visual impairment.

Molecular pathological features: CN and EVN (extraventricular neurocytoma) are defined as distinct entities clinicopathologically, but at the molecular level, the boundary is not always clear. Both tumors have different DNA methylation landscapes and copy number profiles. ¹⁾ The molecular characteristics of CN were not well identified for many years, but recent comprehensive molecular analyses are clarifying its profile. The FGFR1-TACC1 fusion gene is a characteristic marker of EVN, and even if a tumor with this fusion occurs intraventricularly, it is molecularly classified as EVN. ¹⁾

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7. Latest Research and Future Perspectives (Research Stage Reports)

For Patients: Please Read Carefully

The following information is currently at the research stage or under clinical trial and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Advances in Molecular Classification: Redefining the Boundary Between CN and EVN

Clinical application of DNA methylation profiling has revealed cases where conventional pathological diagnosis and molecular diagnosis diverge.

Sato et al. (2023) performed RNA sequencing on one case of lateral ventricular tumor histologically and clinically diagnosed as CN and detected an FGFR1-TACC1 fusion gene. Furthermore, DNA methylation profiling (DKFZ classifier v12.5) classified this case into the EVN class (calibration score 0.99). tSNE analysis clearly separated it from 21 CN cases and formed a cluster with 2 EVN cases. ¹⁾

According to the same study, 13 cases histologically diagnosed as EVN were reclassified into various tumor types such as DLGNT, RGNT, pilocytic astrocytoma, oligodendroglioma, astrocytoma, DMG H3K27M, and GBM by molecular analysis, and 2 cases histologically diagnosed as CN were changed to ganglioglioma by NGS and methylation analysis. ¹⁾ This finding highlights the importance of integrated diagnosis (comprehensive evaluation of imaging, pathology, and molecular findings).

Potential of FGFR Inhibitors as Therapeutic Targets

The majority of EVN harbor FGFR1-TACC1 fusion genes, and FGFR (fibroblast growth factor receptor) is attracting attention as a therapeutic target. ¹⁾ Irreversible FGFR inhibitors (such as futibatinib) are being developed for cholangiocarcinoma, breast cancer, gastric cancer, urothelial carcinoma, esophageal cancer, and non-small cell lung cancer, but clinical data for EVN and CN are not yet available. It should be noted that FGFR mutations are not specific to EVN and are also observed in diffuse astrocytoma, pilocytic astrocytoma, DNET, PXA, PLNTY, and GBM. ¹⁾

Minimally Invasive Neuroendoscopic Surgery Approach

Reports of neuroendoscopic resection for intraventricular tumors are increasing as a less invasive procedure compared to craniotomy. It allows direct visualization within the ventricle and may minimize callosotomy. However, indications for large tumors and long-term outcomes require further investigation. ⁵⁾

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8. References

1. Sato D, Takami H, Takayanagi S, et al. Intraventricular central neurocytoma molecularly defined as extraventricular neurocytoma: a case representing the discrepancy between clinicopathological and molecular classifications. Brain Tumor Pathol. 2023;40:230-234.

2. Mishra S, Phulware RH, Dhiman A, et al. Intraoperative cytologic diagnosis of central neurocytoma mimicking as oligodendroglioma. Indian J Surg Oncol. 2024;15(Suppl 3):S379-S384.

3. Ulzen-Appiah K, Akakpo KP. Central neurocytoma in a teenager, a rare cause of hemiplegia, and a diagnostic dilemma in a resource-poor setting. Case Rep Pathol. 2024;2024:4514981.

4. Johar MA, Dhaif AR, Mahdi A, et al. A young adult with persistent headache: a case of central neurocytoma. Cureus. 2025;17(1):e77470.

5. Aburakawa D, Kanamori M, Akashi T, et al. Corpus callosum swelling after resection of intraventricular central neurocytoma. NMC Case Rep J. 2021;8:535-543.